instructions): Women from different countries who are at high-risk of HIV infection through sexual contact may be protected from infection as a result of acquired immunity to the virus. Several studies demonstrate an HIV- specific humoral immune response in the genital tract of highly exposed, uninfected women. Our hypothesis is that the local immune response in the genital tract in highly exposed seronegative (ESN) women confers protection from infection with HIV. A better understanding of this potentially protective antibody response may provide insight into the role mucosal immunity plays in preventing HIV infection and may help inform Future research related to HIV prevention in women. This goal of this project is to characterize the HIV- specific antibody response in the genital tracts of ESN women from the US and to compare their responses to those of HIV infected elite suppressors and progressors from the Women's Interagency HIV Study (WIHS). We will determine whether the local genital antibody response is more broadly reactive in women who have been repeatedly exposed vaginally but remain uninfected. Preliminary data demonstrate that low concentrations of antibody against HIV are present in the genital fluids of more than 60% of the women in our cohort, many with reactivity against more than one pseudotype of virus. We will (1) characterize local genital tract binding and neutralizing antibodies in our cohort of high risk, seronegative women, including characterization of neutralizing antibodies that bind to broadly neutralizing epitopes (2) evaluate the durability of antibodies in the genital tract including ADCC, ADCVI and cross clade ADCC activity, (3) compare the specificity and frequency of antibodies in the genital tract of ESN women with HIV infected progressors and elite suppressors from the WIHS cohort, and (4) compare the humoral immune response in the genital tract of ESN women from Rwanda with those of ESN women from the US. It would be extremely valuable to know the particular components of the genital immune response that protect against heterosexual transmission of HIV. This knowledge could be used to develop a vaccine that effectively and selectively stimulates protective local immunity in the female genital tract against HIV infection. RELEVANCE (See instructions): Exposed seronegative women (ESN) with heterosexual exposure from multiple partners have antibodies in their genital tract against HIV. We will characterize their response and compare it to that of women who were infected following exposure. If these studies reveal differences in the types of antibodies produced by these women, it could help us understand the type of antibody needed for protection against HIV infection.